A systematic review and bioinformatic study on clinical, paraclinical, and genetic factors predisposing to stent restenosis following percutaneous coronary intervention

Background Stent restenosis is a relatively common phenomenon among patients with coronary heart disease undergoing percutaneous coronary intervention (PCI). It seems that a set of clinical, laboratory, and even genetic factors make people susceptible to such a phenomenon and in fact, this is multi-factorial. We aimed to first determine the underlying clinical and laboratory risk factors for the occurrence of stent re-stenosis after PCI based on a systematic review study, and after that, through a bioinformatics study, to evaluate the related genes and microRNAs with the occurrence of stent re-stenosis. Main text In the first step, the manuscript databases including Medline, Web of Knowledge, Google Scholar, Scopus, and Cochrane were deeply searched by the two blinded investigators for all eligible studies based on the considered keywords to introduce clinical and laboratory determinants of stent re-stenosis. In the bioinformatic phase, and following a review of the literature to identify genes and microRNAs involved in restenosis, the interaction of each gene with other genes associated with stent re-stenosis was determined by GeneMANIA network analysis and Cytoscape software. Overall, 67 articles (including 40,789 patients) on clinical and biochemical predictors for stent restenosis and 25 articles on genetic determinants of this event were eligible for the final analysis. The predictors for this event were categorized into four subgroups patient-based parameters including traditional cardiovascular risk profiles, stent-based parameters including type and diametric characteristics of the stents used, coronary lesion-based parameters including several two target lesions and coronary involvement severity and laboratory-based parameters particularly related to activation of inflammatory processes. In the bioinformatic phase, we uncovered 42 genes that have been described to be involved in such a phenomenon considering a special position for genes encoding inflammatory cytokines. Also, 12 microRNAs have been pointed to be involved in targeting genes involved in stent re-stenosis. Conclusions The incidence of stent re-stenosis will be the result of a complex interaction of clinical risk factors, laboratory factors mostly related to the activation of inflammatory processes, and a complex network of gene-to-gene interactions.


Background
Ischemic coronary heart disease is the result of an imbalance between blood distribution and tissue demand in the myocardial muscle.Coronary artery lumen narrowing due to atherosclerosis is responsible for about 98% of ischemic heart disease cases [1].It should be noted that coronary heart disease mainly affects the age group of 35 to 65 years, and in an important part of society, conflict may occur at the level of young people.In addition, coronary heart disease accounts for 64% of all cardiovascular deaths.According to the published statistics, during the last decade, we have seen an increase in the morbidity caused by ischemic cardiovascular diseases [2].Of course, it should be kept in mind that with the development of medicinal methods as well as therapeutic interventions such as angioplasty and coronary stenting, the frequency of morbidity and mortality cases caused by these diseases has decreased significantly [3].The first case of stent implantation was performed in 1986 and after that percutaneous coronary intervention or PCI was listed as one of the standard treatment strategies for these disorders [4].Today, these methods as endovascular treatments aimed at restoring coronary blood flow have led to the lives of millions of people.However, observations have shown that within 6 months to one year after successful coronary stenting, there is a possibility of angina recurrence due to restenosis of the stent [5].This issue has even been reported for drug-eluting stents [6].After initial coronary stenting, the prevalence of restenosis is between 20 and 30% [7].This stent restenosis occurs for various clinical and even genetic reasons and it seems that a set of pathophysiological processes such as inflammatory processes, proliferation, genomic and epigenetic factors play a role in it [8].But interestingly, the role of each of these factors can be very different in different societies.In particular, the impact of genetic factors is completely dependent on the demographic characteristics of that society.Today, all kinds of genes, genetic polymorphisms, and microR-NAs have been identified and introduced in the incidence of stent re-stenosis, which, along with clinical risk factors, double the risk of this complication.We aimed to first determine the underlying clinical and laboratory risk factors for the occurrence of stent re-stenosis after PCI based on a systematic review study, and after that, through a bioinformatics study, to evaluate the related genes and microRNAs with the occurrence of stent re-stenosis.

Systematic review phase
The present systematic review and meta-analysis followed the guidelines for the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).Firstly, two questions were suggested based on the author's purposes "What are the main clinical determinants for stent re-stenosis?" and "What are the related and predictive genetic factors for re-stenosis?".In the next step, the manuscript databases including Medline, Web of Knowledge, Google Scholar, Scopus, and Cochrane were deeply searched by the two blinded investigators for all eligible studies based on the considered keywords including "stent", "stenosis", "re-stenosis", "predictor", "risk factor", "gene", "genetics", and "microRNA".The inclusion criteria were considered to retrieve the studies: (1) the studies finally assessed clinical and/or genetic-based risk profiles related to stent re-stenosis, (2) due to the potential effects of other cardiac revascularization procedures such as coronary artery bypass grafting, those studies entering the patients who undergo such revascularization procedures or previous history of cardiac procedures were all excluded from analysis, (3) The studies were restricted to the English language, (4) the studies with unclear or irreproducible results were all excluded, (5) lack of access to the manuscripts full texts were also considered as the inclusion criteria unless the abstracts had enough data for our analysis, (6) case reports, case series, and review papers were all excluded.As shown in the flow diagram of the study selection (Fig. 1), 1536 articles were initially collected by database searching.After removing 13 articles due to evidence of duplication, 1523 records were primarily under-screened.Based on the titles and abstracts, 1426 records were excluded and the remaining 97 citations were assessed for further eligibility.Of those, 5 were also excluded due to the incompleteness of the data and contents.In the final, 67 articles on clinical and biochemical predictors for stent restenosis  (Table 1) and also 25 articles on genetic determinants of this event were eligible for the final analysis  (Table 2).
Data abstraction was independently performed by two un-blinded reviewers on structure collection forms without divergences in data collection.We resolved disagreements by consensus or by involving a third person.The study quality was evaluated based on the following criteria: (1) the systematic review and meta-analysis based on the questions primarily described and formulated; (2) inclusion and exclusion criteria predefined in the studies as eligibility criteria; (3) searching the literature performed on a systematic and comprehensive approach; (4) to minimize the bias, the full texts of the article were dually reviewed; (5) the quality of included studies were rated independently by the reviewers for appraising internal validity; (6) studies' characteristics and findings were comprehensively listed; (7) the publication and risk of bias were listed; and (8) heterogeneity was also assessed.The risk of bias for each study was assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions and also according to the QUA-DAS-2 tool.Any disagreement was resolved by discussion with the whole study team.

Bioinformatic phase
The details of bioinformatic processing to assess the genes and gene-gene interactions are described by Sheikhvatan et al. previously [102].Briefly, the interaction of each gene with other genes associated with stent re-stenosis was determined by GeneMANIA software (https://genemania.org/)indexing 2277 association networks containing more than 500 million interactions mapped to 163.599 genes in humans.The interactions were calculated based on FDR (False Discovery Rate) and coverage was classified under four categories (a) Shared protein domains, (b) Co-expression, (c) Co-localization, and (d) Genetic interactions.In this regard, a FDR ≤ 5% was considered to be significant.To design an integrated model of a gene interaction network, the Cytoscape software (version 3.6.1.0)was applied.

Discussion
Stent re-stenosis after primary stenting in patients with acute coronary syndrome is an uncommon but multifactorial phenomenon.This phenomenon is created and expanded as a result of the interaction of a set of clinical and laboratory factors as well as genetic predisposing factors.Obviously, due to the multifactorial nature of this incident, it will not be possible to accurately determine its prevalence.On the other hand, for the same reasons, it will not be possible to accurately estimate the occurrence of such an event.In this regard and based on a review of the literature, a wide set of background factors are involved in the occurrence of stent restenosis.Among the clinical factors, the presence of classic underlying risk factors of cardiovascular diseases has been completely predictable, in such a way that the risk of stent re-stenosis is higher in elderly patients, obese patients, hypertensive and diabetic patients, patients with hyperlipidemia, as well as patients with The history of chronic renal failure as well as the history of ischemic heart disease have been completely predictable.Also, among the laboratory risk factors, a special place can be given to inflammatory markers, because the occurrence of atherosclerosis is also the result of the interaction between underlying risk factors and inflammatory factors, and such a process can also be predicted in the case of stent re-stenosis.The basis of the occurrence of such a complication has a strong link with the activation of the inflammatory cascade.Additionally, the genomic polymorphisms have also provided the basis for the emergence and spread of stent restenosis.In this direction and during the last two decades, efforts have been made to identify the genetic factors related to the occurrence of this event using various genetic techniques, to identify types of gene polymorphisms, changes in the expression of various genes, and also to identify microRNAs related to it, which play an important role in the changes of the targeted genes involved.There is growing evidence of genetic contribution to vascular remodeling and ultimately coronary calcification and atherosclerosis through extracellular matrix changes and also MicroRNAs involvement in endothelial cell and vascular smooth muscle dysfunction in diabetic patients which makes it an interesting topic to evaluate in the context of in-stent restenosis.

Conclusions
Therefore, it seems that the incidence of stent re-stenosis will be the result of a complex interaction of clinical risk factors, laboratory factors mostly related to the activation of inflammatory processes, and a complex network of gene-to-gene interactions, and therefore, it will not be possible to indicate on only one or a limited number of predisposing factors.However, special attention to some background factors can be considered.For example, identifying and tracking increased expression or discovering polymorphisms related to genes encoding various types of inflammatory interleukins can provide a way for early diagnosis and prevention of this complication.It is also obvious that controlling the traditional risk factors of cardiovascular diseases will be successful in preventing the occurrence of such a complication.

Fig. 1
Fig. 1 gene to gene interaction involving stent restenosis

Table 1
Reviewing the studies on the predictors of stent restenosis all 67 studies yielded good quality and none of the cita- tions was determined to have a high risk of bias therefore the pooled results should be persuasive.In total, 40,789 patients were assessed and scheduled for primary stenting for coronary artery disease and followed up for 6 to 36 months after the procedure for assessing the occurrence of stent restenosis and its main determinants.The predictors for this event might be categorized as the four subgroups including (1) patient-based parameters including history of diabetes mellitus, hypertension, hyperlipidemia, smoking, history of tenting, chronic renal failure, history of non-alcoholic fatty liver disease, higher age, medical history of COPD, history of PCI, higher body mass index, low physical activity, Type D personality,

Table 1 (
continued) anger, and some nutritional habits including lower folate intake, low fruit intake, low vegetable intake, and low vitamin C ingestion; (2) stent-based parameters including type of stent (BMS versus DES), lower stent diameter, longer stent, (3) coronary lesion-based parameters including two target lesions, Gensini score, TIMI score, coronary artery calcium score, coronary artery diffuse disease, peripheral vascular lesions, bifurcation lesion, CHA2DS2-VASc score, calcified plaque volumes, plaque burden, remodeling index, multiple stenting, stents in left

Table 2
The genes, polymorphisms, and miRNAs related to stent restenosis